1. Field of the Invention
The present invention relates to a method for treating (ex vivo) blood, blood products and organs for preventing the transmission of Alzheimer's disease and other amyloid-based diseases.
2. Discussion of Background Information
On account of the demographic development within the next few decades, the number of people suffering from age-related diseases will increase. Mention is to be made here in particular of so-called Alzheimer's disease (AD, Alzheimer dementia, Latin=Morbus Alzheimer).
One feature of Alzheimer's disease is extracellular deposits of the amyloid-beta peptide (A-beta peptide, Aβ, or Aβ peptide). This deposition of the A-beta peptide in plaques is typically determined in the brains of AD patients post mortem. Consequently, various forms of the A-beta peptide—such as e.g. fibrils—are deemed to be responsible for the onset and the progress of the diseases. Additionally, for some years, the small, freely diffusible A-beta oligomers have been considered to be primary causes of the onset and the progress of AD. A-beta monomers, as building blocks of the A-beta oligomers are continually formed in the human body and are presumably per se nontoxic. A-beta monomers can inadvertently cluster depending on their concentration. The concentration is dependent on their formation and degradation rate in the body. If an increase in the concentration of A-beta monomers takes place in the body with increasing age, a spontaneous clustering of the monomers to A-beta oligomers is all the more probable. The A-beta oligomers thus formed could replicate analogously to the prions and ultimately lead to Alzheimer's disease.
An important difference between prevention and treatment or even healing of AD lies in the fact that prevention can be achieved merely by preventing the formation of the first A-beta oligomers. For this, a few A-beta ligands are sufficient which have lower affinity and are less selective as regards the A-beta oligomers.
The formation of the A-beta oligomers from many monomers is a reaction of high order and thus dependent to a high degree on the A-beta monomer concentration. Consequently, even a small reduction in the active A-beta monomer concentration leads to a prevention of the formation of the first A-beta oligomers. This mechanism has hitherto been the basis of prevention.
When treating AD, however, a completely altered situation is assumed. This is because here A-beta oligomers or possibly also even larger polymers or fibrils are present which have formed by the prion-like replication of the oligomers. However, this is a reaction of low order and barely dependent on the A-beta monomer concentration.
Hitherto, no approved medicament exists for a causal treatment of Alzheimer dementia (AD). Typically, deposits of the so-called beta-amyloid peptide (Aβ or A-beta) are found in plaques in the brains of AD patients post mortem. Consequently, various forms of the Aβ oligomers, e.g. fibrils, have for a long time already been considered to be responsible for the onset and the progress of AD. For a few years, particularly the small, freely diffusible Aβ oligomers have been held responsible as the main causes of the onset and the progress of AD. Aβ monomers are continuously formed in the human body and are presumably per se nontoxic. It is speculated whether Aβ monomers inadvertently cluster as a function of their concentration and thus with increasing age ever more probably spontaneously to give Aβ oligomers. Aβ oligomers, once formed, could replicate by means of a prion-like mechanism and ultimately lead to the disease. For some time, it has been discussed whether AD—similarly to prion diseases—is in principle transmissible from person to person. The same applies to all amyloid-associated diseases (e.g. Parkinson's). In particular, a possible transmission by means of blood transfusion, administration of blood products and organ transplants could lead, without suitable tests and prevention methods, to a massive risk to the health of recipients. In this connection, there has been a report in the nonscientific literature of the premature onset of AD in a transgenic mouse after its complete blood was exchanged for that of a diseased mouse.
On account of these considerations, it should be an option to free blood, blood products and organs from infectious particles by means of (prophylactic or preventative) treatment, or to deactivate these. It should in this connection be the aim to entirely remove or to destroy, i.e. to detoxify, toxic Aβ oligomers and to thereby prevent their prion-like replication.
The prior art discloses various methods for eliminating biohazardous materials, bioparticles, molecules and pathological protein deposits. For example, there is research according to which nanomagnets are used in order to purify blood in a targeted manner from a hazardous material within a few minutes. Similarly, it has been described to remove LDL cholesterol from the blood by means of direct absorption of lipoproteins (DALI).
The immobilization of antibodies or peptides is described in DE 600 26 983 T2 or U.S. Pat. No. 5,968,820.
Furthermore, DE 102009037015 A1 discloses a device and a method for eliminating biohazardous substances from body fluids. The isolation of cells, bioparticles and molecules from liquids is described in DE 102005063175 A1. Furthermore, DE 102005031429 A1 discloses a method for the selective determination of pathological protein deposits. Finally, DE 102005009909 A1 describes compounds for treating diseases in connection with incorrectly folded proteins.
The substances known from the prior art reduce the concentration of A-beta monomers and/or oligomers in a very wide variety of ways. Thus, e.g. gamma-secretase modulators are known which were used in animal experiments for prevention.
WO 02/081505 and DE 101 17 281 A1 discloses various sequences of D-amino acids which bind to A-beta peptides. These sequences in WO 02/081505 from D-amino acids bind to amyloid-beta peptides with a dissociation constant KD value of 4 μM.
WO 2011/147797 discloses hybrid compounds consisting of aminopyrazoles and peptides which prevent A-beta oligomerization.
A use of these compounds for purifying blood, blood products and/or organs, however, is not disclosed.
For many substances which have shown positive results in animal experiments, this effect could not be confirmed in clinical studies on humans. In phase II and III clinical studies, only people diagnosed with clear AD are allowed to be treated. Here, a slight decrease in the A-beta monomer concentration no longer suffices to prevent larger amounts of A-beta oligomers, and/or to influence the course of the disease.
Hitherto, Alzheimer dementia has primarily been diagnosed by neuropsychological tests, by experiments on people in which the symptoms were already recognized. However, it is known that A-beta oligomers and the subsequent fibrils and plaques are formed up to 20 years before the onset of the symptoms in the brain of the patients, and may have already caused irreversible damage. However, there is hitherto still no possibility of diagnosing AD before the onset of symptoms.
It is now an object of the present invention to free blood, blood products and/or organs by treatment of toxic and/or infectious particles, or to deactivate these. It is the aim to completely remove the Aβ oligomers present in blood, blood products or organs, or to convert them to nonharmful forms.